Several biodegradable polymers have found use in the field of tissue engineering, because of their attractive physical, chemical, biological and mechanical properties. Polymers useful in tissue engineering may be divided into the groups of natural polymers and synthetic polymers.
Natural polymers include, but are not limited to, collagen, hyaluronic acid, alginate, gelatin, xanthan gum, keratin, and small intestinal submucosa. These polymers have good biocompatibility and are unlikely to induce an immune response after transplantation. However, the mechanical properties of natural polymers are not completely satisfactory.
Synthetic polymers include, but are not limited to, PLA (poly(lactic acid)), PGA (poly(glycolic acid)), PLGA (poly(lactic-co-glycolic acid)) and PCL (poly(ε-caprolactone)) and are mainly hydrophobic polyesters. Among them, PGA and PLA (both of which are comprised of α-hydroxy acid monomers) and their copolymer PLGA are synthetic polymers approved by the U.S. FDA for biomedical applications. PGA, PLA and PLGA are widely used as porous tissue scaffolds and drug delivery systems, and have high biocompatibility, biodegradability and processability. However, these synthetic polymers do not adhere well to cells, because they lack biologically active components and are hydrophobic. Acids produced during the hydrolysis of PLGA reduce the pH of the surrounding tissue, causing inflammation. Further, these polymers are incapable of targeting a specific site or responding to the environment of a diseased site.
Vanillyl alcohol (also known as 4-(hydroxymethyl)-2-methoxyphenol; 3-methoxy-4-hydroxybenzyl alcohol; 4-hydroxy-3-methoxybenzenemethanol; 4-hydroxy-3-methoxybenzyl alcohol; vanillic alcohol; vanillin alcohol; or “VA”), a phenolic compound found in plant roots, tomatoes and carrots, and is the main component of Gastrodia elata, used to treat headaches and cancer in traditional Chinese medicine. In recent years, the medicinal effects and properties of natural vanillyl alcohol and vanillyl derivatives have been studied.
Oxidative stress has been shown to be involved in the development of many disease states including cancer, neurodegenerative disease, transplantation, end stage renal disease and atherosclerosis/heart failure. Oxidative stress injury occurs when there is an increased production of oxidizing species simultaneously with a reduction in antioxidant defenses resulting in the manifestation of reactive oxygen species (ROS). Reperfusion of a previously ischemic tissue is a prominent disease pathway in the development of a large amount of ROS. This overwhelms the cellular defense system and subsequently damages normal cellular functions that can ultimately lead to death. In particular, hydrogen peroxide (H2O2), the most abundant form of the ROS produced during ischemia/reperfusion (I/R), plays an important role by inducing the release of pro-inflammatory cytokines and apoptosis which further potentiate tissue damage. Since the amount of tissue damage is the most important determinant of morbidity and mortality associated with ischemic diseases, limiting cellular death is a paramount approach for favorable outcome in these conditions. Excess amount of H2O2 that exceeds local antioxidant capacity determines the susceptibility for oxidative damage. Therefore, focusing locally on H2O2 production is a therapeutically relevant way that could stop oxidative stress injury in a variety of disease pathologies.
Oxidative stress plays a major role in cardiac dysfunction leading to a variety of ailments including heart failure thereby resulting in the need of major surgery. In 2011 nearly 11% of US adults had been diagnosed with cardiovascular disease, where more than 50% will also experience co-morbidities such as hypertension and stroke. Although cardiovascular disease has diverse etiology, the primary induction of disease onset is atherosclerosis, the occlusion of primary vessels that carry blood supply to and from the heart. As the disease progresses there will be continued blockage of the arteries leading to necessary procedures such as cardiopulmonary bypass surgery (CPB) or coronary artery bypass graft (CABG) whereby new vessels are either diverted or created in order to bypass those already occluded with plaque allowing for improved circulation. Nearly 2% of US adults, or 395,000 individuals, require a CABG procedure annually in order to forgo life-threatening events such as cardiac arrest.
CABG is a major surgical procedure that requires lengthy hospital stays and likely results in post-operative ischemia or reperfusion-related complications. Complications associated with oxidative damage during CABG (with respective % incidence) include, but are not limited to, atrial fibrillation (up to 40%), infarct extension: reocclusion of an infarct-related artery (IRA) (5-30%), recurrent infarction (17-25%), arrhythmia (13.6%), renal function decrease (5-10%), stroke (6.1%), small-to-moderate MI (2-4%), ventricular tachycardia/fibrillation (2-3%), congestive heart failure (2.4%), GI dysfunction (2.3%), and acute renal failure (0.7%).
Nearly 15% of those patients develop perioperative complications, specifically ischemia and/or reperfusion injury, adding at least an additional $10,000 per patient. Adding insult to injury, one of the main pathogenic mechanisms following CABG surgery is subsequent ischemia/reperfusion (I/R) injury, which can appear as reocclusion of an infarct-related artery (IRA). Approximately 5-30% of patients experience infarct extension and 17-25% of patients likely experience early IRA. Patients who experience I/R can also clinically present symptoms that include arrhythmias (13.6%) combined with myocardial and microvascular stunning, and hemorrhage (5.6%) often being indistinguishable from the initial injury. Moreover, myocardial necrosis, a clear result of I/R, has been present in a majority of CPB patients with fatal outcome.
There is a need in the art to develop novel biodegradable polymers that are useful in tissue engineering and other biomedical applications. Such polymers should display good mechanical properties and biocompatibility.